Section of Toxicology and Biomedicine, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Santa Maria di Galeria, 00123 Rome, Italy.
J Immunol. 2010 Apr 1;184(7):3470-7. doi: 10.4049/jimmunol.0901568. Epub 2010 Mar 5.
Growing evidence is unveiling a role for poly(ADP-ribose) polymerase (PARP)-1 in the regulation of inflammatory/immune responses. In the current study, we investigated the effects of PARP-1 deficiency on regulatory T cell differentiation. Increased numbers of regulatory CD4(+)CD25(+)/Foxp3(+) T cells were found in thymus, spleen, and lymph nodes of PARP-1 knockout (KO) mice compared with wild-type (WT) controls. The increased frequency of regulatory T cells in the periphery resulted in impaired CD4 cell proliferation and IL-2 production, which could be restored by CD25(+) cell depletion. Phenotype and inhibitory functions of PARP-1 KO regulatory T cells were similar to WT cells, indicating that PARP-1 affects regulatory T cell differentiation rather than function. Purified naive CD4 cells from PARP-1 KO mice stimulated in vitro expressed forkhead box p3 mRNA at higher levels and generated a greater number of Foxp3(+) cells (inducible regulatory T [iTreg] cells) than the WT counterpart. This finding was due to a higher rate of naive CD4 cell to Foxp3(+) iTreg cell conversion rather than to higher resistance to apoptosis induction. Interestingly, PARP-1 deficiency did not affect retinoid-related orphan receptor-gammat mRNA expression and differentiation of purified naive CD4 cells to Th17 cells. PARP-1 KO iTreg cells showed features similar to WT regulatory T cells, suggesting that modulation of PARP-1 during the immune response might be used to induce greater numbers of functional regulatory T cells. In conclusion, our findings represent the first evidence that PARP-1 can affect regulatory T cell differentiation and open new perspectives on potential targets for modulating immune responses.
越来越多的证据表明，多聚（ADP-核糖）聚合酶 1（PARP-1）在调节炎症/免疫反应中发挥作用。在本研究中，我们研究了 PARP-1 缺乏对调节性 T 细胞分化的影响。与野生型（WT）对照相比，PARP-1 敲除（KO）小鼠的胸腺、脾脏和淋巴结中调节性 CD4+CD25+/Foxp3+T 细胞数量增加。外周血中调节性 T 细胞的频率增加导致 CD4 细胞增殖和 IL-2 产生受损，这可以通过 CD25+细胞耗竭来恢复。PARP-1 KO 调节性 T 细胞的表型和抑制功能与 WT 细胞相似，表明 PARP-1 影响调节性 T 细胞分化而不是功能。体外刺激来自 PARP-1 KO 小鼠的幼稚 CD4 细胞表达更高水平的叉头框 P3 mRNA，并产生更多的 Foxp3+细胞（诱导性调节性 T [iTreg]细胞）比 WT 对照。这一发现是由于幼稚 CD4 细胞向 Foxp3+iTreg 细胞转化的速度更高，而不是对凋亡诱导的抵抗力更高。有趣的是，PARP-1 缺乏不影响视黄酸相关孤儿受体γt mRNA 的表达和纯化的幼稚 CD4 细胞向 Th17 细胞的分化。PARP-1 KO iTreg 细胞表现出与 WT 调节性 T 细胞相似的特征，这表明在免疫反应期间调节 PARP-1 可能用于诱导更多功能调节性 T 细胞。总之，我们的研究结果首次表明 PARP-1 可以影响调节性 T 细胞分化，并为调节免疫反应的潜在靶点提供了新的视角。
